Individuals with type 2 diabetes are at risk for well-known comorbidities (e.g., heart, kidney, and eye diseases, neuropathy, and cognitive disorders) that have been thoroughly discussed in the American Diabetes Association (ADA) Standards of Care in Diabetes. The risk associated with nonalcoholic fatty liver disease (NAFLD) was not mentioned in the ADA Standards of Care until recently; the 2023 ADA guidelines now have nearly four pages devoted to NAFLD (1). The issue of risk factors associated with NAFLD has also been the focus of U.S. and European guidelines, largely promoted by liver disease associations that are well aware of the impact of metabolic components (namely, type 2 diabetes and obesity) on the long-term development of nonalcoholic steatohepatitis (NASH), NASH cirrhosis, and NASH-associated hepatocellular cancer (2,3). The liver plays a central role in glucose homeostasis and diabetes development by controlling fasting and postprandial glycemia through glucose production in the fasting state and glucose storage as glycogen during the postprandial state. The liver is also central to lipid and lipoprotein metabolism, as it is responsible for the synthesis and secretion of triglycerides and lipoproteins, which are the major risk factors for cardiovascular diseases. This explains the intertwined connection among NAFLD, diabetes, and cardiovascular diseases and the evidence that makes NAFLD a leading cause of years of working life lost, second only to ischemic heart disease, in the European and American regions (4).
NAFLD prevalence is extremely high in the global population and continues to increase from the initial estimate of 25% (1989–2016) to 34–38% more recently (2021 data) (5,6). The diagnosis is based on evidence of liver steatosis (usually by ultrasounds) without other causes of liver diseases (e.g., viral hepatitis) and/or steatogenic factors, i.e., drugs (3,7,8), and exclusion of alcohol, as this is the second most common cause of fatty liver even in the presence of light to moderate consumption (2). Needless to say, alcohol consumption and metabolic alterations such as insulin resistance may coexist, increasing the risk of liver fat accumulation. Progression to NASH requires the demonstration of hepatic necroinflammation and fibrosis. Whereas fibrosis may be diagnosed by serum biomarkers (fibrosis-4 score [FIB-4], NAFLD fibrosis score, and enhanced liver fibrosis test) and imaging techniques (vibration-controlled transient elastography [VCTE]) with sufficient accuracy (9), the severity of necroinflammation can be assessed only by liver biopsy (3,7). Given its invasiveness, poor acceptance, and risks for patients, the procedure is frequently limited to individuals with elevated liver enzymes, as these people are alleged to have more severe disease. Accordingly, NASH remains a “silent” disease, although NASH and fibrosis can occur even in individuals with liver enzymes below the upper limit of normal, i.e., plasma ALT <40 units/L (10). This is also the case for adults with type 2 diabetes, for which data on NASH are highly variable, although individuals with diabetes, obesity, or other metabolic alterations are at higher risk of NASH, advanced fibrosis (F3–F4), and cirrhosis (F4) (11).
In this issue of Diabetes Care, the study by Castera et al. (12) provides a timely assessment of the real impact of severe liver disease in type 2 diabetes. The prevalence of NASH and advanced fibrosis was tested in a large group of outpatients who were initially screened for NAFLD in four diabetology units in France and then referred to the hepatologists for further exams. Indication for liver biopsy was based on prespecified standardized criteria, namely, ALT persistently above the low cutoff of 20 units/L in female individuals or >30 units/L in male individuals, in the absence of other causes of liver disease. A total of 360 individuals of the 713 initially referred to the hepatologists agreed to undergo a liver biopsy, and 330 samples were included in the final analysis. NASH (58%), advanced fibrosis (38%), and cirrhosis (10%) (see Graphical Abstract) were common, although one-third of the individuals had minimally elevated ALT (between 20 and 40 units/L). This confirms the relevance of reducing the threshold for abnormal ALT levels, which was initially advocated by Prati et al. in 2002 (13) and recently promoted by the ADA in the 2023 Standards of Care (1). Finally, based on the data from their sample, Castera et al. (12) developed a score that predicts NASH and advanced fibrosis, with an area under the receiver operating characteristic curve of 0.81 and 0.77, respectively. Both models included parameters associated with metabolic syndrome (i.e., large waist, hypertension, and high triglyceride and low HDL levels) (see Graphical Abstract); AST levels were included in the NASH model and γ-glutamyl transferase levels were included in the model for advanced fibrosis, but ALT levels were excluded. The use of data derived by VCTE minimally increased the predictive ability of tests and did not justify the extra cost of tests (2).
The study has several strengths. It addresses the unmet need for early and accurate NASH diagnosis in a large cohort of patients with type 2 diabetes, providing a screening strategy based on routine markers that can be readily accessible in most diabetes clinics. Among the parameters of the suggested scores, only serum albumin is infrequently tested. Validation in independent cohorts with different metabolic characteristics is needed, although the histological results are paralleled by data retrieved in a prospective study of 501 U.S. adults with type 2 diabetes aged ≥50 years who were tested by magnetic resonance imaging and elastography (prevalence of NAFLD, 65%; advanced fibrosis, 14%; cirrhosis, 6%; two instances of hepatocellular cancer and one of gallbladder cancer were found) (14). Notably, both studies showed that advanced fibrosis may be underestimated by VCTE and FIB-4 (12,14). Higher levels of HbA1c were observed in NASH versus no NASH (7.7% vs. 7.4%) (12) and in NAFLD versus no NAFLD (6.9% vs. 6.5%) (14), whereas HbA1c was not different in relation to advanced fibrosis. It would be interesting to compare the French scores with the fibrotic NASH index that was recently developed (15), which combines HbA1c, AST, and HDL to predict fibrotic NASH and is validated against liver biopsy in individuals with morbid obesity who are eligible for bariatric surgery.
The most important result of the French study is the definite histological evidence that NASH and NASH cirrhosis may occur despite normal or near-normal liver enzymes in patients with type 2 diabetes, which conflicts with the well-accepted paradigm that elevated enzymes are a criterion for additional diagnostic tests. Does this mean that we need to screen all individuals with type 2 diabetes for NASH and advanced fibrosis? This approach was initially considered impossible to pursue and not cost-effective (16), but surrogate biomarkers and VCTE, the use of which is widespread, are now considered valid tests for referral (9,17,18). Certainly, it is mandatory to screen for the presence and severity of NAFLD in all adults with type 2 diabetes with liver enzymes in a wider range than usually considered.
A few questions remain. The final evaluation covered a limited portion of patients initially screened according to ADA recommendations (elevated serum enzymes and steatosis on ultrasound) despite very conservative limits. This means that liver enzymes fluctuate and more stringent criteria for selection are needed. The patients screened by Castera et al. (12) might be the tip of the iceberg of the population with both diabetes and liver disease, and the predictive models might behave differently in the presence of different a priori risks. Whatever the risk, we now know that the possible progression to NASH and cirrhosis is another reason to optimize metabolic control with novel glucose-lowering drugs, as both single and dual incretin receptor agonists and sodium–glucose cotransporter 2 inhibitors have been proven to reduce steatosis (1), and the search for compounds able to modify fibrosis covers several pages in the ClinicalTrials.gov database.
See accompanying article, p. 1354.
Duality of Interest. G.M. has received speaker’s honorarium from Eli Lilly. A.G. has served as a consultant for Boehringer Ingelheim, Pfizer, Fractyl Health, and Merck Sharp & Dohme; has participated in advisory boards for Boehringer Ingelheim, Pfizer, and Novo Nordisk; and has received speaker’s honorarium and other fees from Eli Lilly, Novo Nordisk, and Pfizer. No other potential conflicts of interest relevant to this article were reported.